ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6877T>C (p.Phe2293Leu) (rs80358912)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045083 SCV000073096 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 2293 of the BRCA2 protein (p.Phe2293Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs80358912, ExAC 0.05%). This variant has been observed in individuals with personal or family history of breast and/or ovarian cancer (PMID: 12442275, 30262796). This variant is also known as 7105T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 52216). An experimental study has shown that a BRCA2 peptide carrying this missense change does not significantly alter BRCA2 function in cell culture, although the clinical significance of these findings is unclear (PMID: 21741379). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000132016 SCV000187075 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter clinical testing The p.F2293L variant (also known as c.6877T>C), located in coding exon 11 of the BRCA2 gene, results from a T to C substitution at nucleotide position 6877. The phenylalanine at codon 2293 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in multiple Mexican patients with breast cancer (Ruiz-Flores P et al. Hum. Mutat. 2002 Dec;20(6):474-5; Calderón-Garcidueñas AL et al. Salud Publica Mex. 2005;47(2):110-5; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10). The functional significance of this alteration was examined using a cell survival assay and an apoptotic index assay, wherein this alteration was shown to exhibit higher survival and no difference in apoptosis levels when compared to a control (Warren CR et al. Exp. Cell Res. 2011 Sep;317(15):2099-109). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174215 SCV000225478 uncertain significance not provided 2014-12-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132016 SCV000683825 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765133 SCV000896359 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779926 SCV000916853 likely benign not specified 2020-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6877T>C (p.Phe2293Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249144 control chromosomes, predominantly at a frequency of 0.0005 within the Latino subpopulation in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.0005 vs. 0.00075), however, it may still suggest this is a rare polymorphism found primarily in the populations of Latino origin. c.6877T>C has been reported in the literature in individuals of Mexican descent who were affected with Hereditary Breast and Ovarian Cancer (Ruiz-Flores_2002, Calderon-Garciduenas_2005, Quezada_2018), however without strong evidence for causality (such as co-segregation data). These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant was also found in a healthy control of Latino origin (Zayas-Villanueva_2019). Co-occurrences with other pathogenic variants have been reported (in the BIC database: BRCA1 c.798_799delTT (p.Val266_Ser267ValLysfs); and in an internal LCA sample: BRCA2 c.6078_6079delAA (p.Glu2028fsX20)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function evaluating cell survival and apoptotic index of stably transfected cell lines treated with cisplatin. These results showed no damaging effect of this variant (Warren 2011). Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282827 SCV001158078 uncertain significance none provided 2020-04-13 criteria provided, single submitter clinical testing The BRCA2 c.6877T>C; p.Phe2293Leu variant (rs80358912) is reported in the literature in several individuals affected with breast cancer (Calderon-Garciduenas 2005, Quezada Urban 2018, Ruiz-Flores 2002). This variant is found in Latino population with an overall allele frequency of 0.05% (17/34230 alleles) in the Genome Aggregation Database. The phenylalanine at codon 2293 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, a peptide containing this variant exhibited apoptotic effects on cultured cells similar to a wildtype peptide (Warren 2002), although the physiological relevance of this assay is uncertain. Due to limited information, the clinical significance of the p.Phe2293Leu variant is uncertain at this time. References: Calderon-Garciduenas AL et al. Clinical follow up of mexican women with early onset of breast cancer and mutations in the BRCA1 and BRCA2 genes. Salud Publica Mex. 2005 Mar-Apr;47(2):110-5. Quezada Urban R et al. Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility. Cancers (Basel). 2018 Sep 27;10(10). Ruiz-Flores P et al. BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico. Hum Mutat. 2002 Dec;20(6):474-5. Warren CR et al. A new assay for functional screening of BRCA2 linker region mutations identifies variants that alter chemoresistance to cisplatin. Exp Cell Res. 2011 Sep 10;317(15):2099-109.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000174215 SCV001470443 uncertain significance not provided 2019-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000077389 SCV001481641 uncertain significance Breast-ovarian cancer, familial 2 2020-01-07 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000174215 SCV001826199 uncertain significance not provided 2021-02-08 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history of breast cancer (Ruiz-Flores 2002, Quezada Urban 2018); Published functional studies demonstrate no damaging effect: No significant impact on cell growth or cisplatin sensitivity compared to wild type in an in vitro assay (Warren 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as BRCA2 7105T>C; This variant is associated with the following publications: (PMID: 31331294, 30262796, 15889636, 12442275, 21741379)
Sharing Clinical Reports Project (SCRP) RCV000077389 SCV000109186 uncertain significance Breast-ovarian cancer, familial 2 2011-08-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077389 SCV000146967 uncertain significance Breast-ovarian cancer, familial 2 1999-04-12 no assertion criteria provided clinical testing

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